Alkyne-substituted pyridone compounds and methods of use

ABSTRACT

The present invention comprises a new class of compounds capable of modulating the c-kit receptor and, accordingly, useful for treatment of c-kit mediated diseases, including various inflammatory, fibrotic and/or mast cell mediated diseases such as mastocytosis. The compounds have a general Formula I  
                 
 
wherein A 1-3 , R 1  and R 3-6  are defined herein. The invention further comprises pharmaceutical compositions, methods for treatment of c-kit mediated diseases, and intermediates and processes useful for the preparation of compounds of the invention.

This application claims the benefit of U.S. Provisional PatentApplication No. 60/831,088, filed Jul. 14, 2006, which disclosure ishereby incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention generally relates to substituted pyridonecompounds and their use, including use in pharmaceutical formulations,methods of treatment, and methods of preparing medicaments.

BACKGROUND OF THE INVENTION

C-kit is a receptor tyrosine kinase expressed on the surface of mastcells, to which stem cell factor (SCF) is a ligand. Aberrant c-kitsignaling is believed to be a mediator of certain autoimmune diseases.Binding of SCF to the c-kit receptor mediates various functions of themast cell. As an important mediator of mast cell function, C-kit isthought to also play a role in pathologies associated with mast cells(MC). C-kit functions through mast cell generation, which plays animportant role in triggering autoimmune diseases. Mast cells are tissueelements derived from a particular subset of hematopoietic stem cellsthat express CD34, c-kit and CD13 antigens (Kirshenbaum et al., Blood94:2333-2342, 1999 and Ishizaka et al, Curr. Opinion Immunol. 5:937-943,1993). Mast cells are characterized by their heterogeneity, not onlyregarding tissue location and structure but also at the functional andhistochemical levels (Aldenberg and Enerback, Histochem. J. 26:587-596,1994; Bradding et al., J. Immunol. 155:297-307, 1995; Irani et al., J.Immunol. 147:247-253, 1991).

Mast cells are thought to participate in the destruction of tissues byreleasing various proteases and mediators categorized into three groups:pre-formed granule associated mediators (histamine, proteoglycans, andneutral proteases), lipid-derived mediators (prostaglandins,thromboxanes, and leucotrienes), and various cytokines, including IL-1,IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNFα, GM-CSF, MIP-1α, MIP-1b, MIP-2and IFNγ. The liberation of these mediators induces and activatesvarious components of immune response involved in autoimmune diseases,and also promotes the tissue destruction process.

Activation of the auto-immune response is postulated to be caused by, orstimulated from, the degranulation of mast cells. Immature MCprogenitors circulate in the blood stream and differentiate in thetissues. These differentiation and proliferation processes areinfluenced by various cytokines. Stem Cell Factor (SCF) and IFNγ are twocytokines which are important in influencing such processes. The SCFreceptor is encoded by the proto-oncogene c-kit, which belongs to thetype II receptor tyrosine kinase subfamily (Boissan and Arock, J.Leukoc. Biol. 67:135-148, 2000). Ligation of c-kit receptor by SCFinduces its dimerization followed by its transphosphorylation, leadingto the recruitment and activation of various intracytoplasmicsubstrates. IFNγ is another cytokine secreted by mast cells. It has beenreported that IFNγ is responsible for major histocompatibility complexesassociated with autoimmune diseases (Hooks et al., New England J. ofMed., 301:5-8, 1979). These activated substrates induce multipleintracellular signaling pathways responsible for cell proliferation andactivation (Boissan and Arock, 2000).

TNF is another cytokine produced by mast cells. More recently, it hasbeen reported that the TNF produced by mast cells is involved in thepathogenesis of auto-antibody mediated vasculitis (Watanabe et al.,Blood 11:3855-3866, 1994). Mast cells were also shown to controlneutophil recruitment during T-cell mediated delayed-typehypersensitivity reactions through TNF and macrophage inflammatoryprotein 2 (MIP-2). Accordingly, c-kit regulation may be useful invarious types of inflammation including without limitation, rheumatoidarthritis, severe asthma, allergy associated chronic rhinitis, and thelike.

Mast cells have also been implicated in liver allograph rejection(Yammaguchi et al., Hematology 29:133-139, 1999) and in liver fibrosis,where hepatic stallate cells produce the SCF that recruits the mastcells (Gaca et al., J. Hematology 30:850-858, 1999). These observationssuggest that c-kit kinase inhibitors may help prevent organ rejectionand fibrosis. Some possible related c-kit mediated therapeuticindications include idiopathic pulmonary fibrosis (IPF) and scleroderma.Mast cells have also been implicated in the pathology of multiplesclerosis (Secor et al., J. Experimental Medicine 191:813-822, 1999),and ischemia-reperfusion injury (Andoh et al, Clinical & ExperimentalImmunology 116:90-93, 1999) in experimental models using mice withmutant Kit receptors that are deficient in mast cells. In both cases,the pathology of the diseases was significantly attenuated relative tomice with normal c-Kit and mast cell populations. Thus, the role of mastcells in these diseases suggests that c-Kit modulators might be usefultherapeutics.

C-Kit signaling is also important for fetal gonadal development, andplays a role in adult fertility (Mauduit et al, Human Rep. Update 5:535-545, 1999). Spermatogenesis is inhibited through a reduction ofc-Kit activity in c-kit signaling through the PI3 kinase pathway(Blume-Jensen et al, Nature Genetics 24:157-162, 2000). C-kit expressionhas been observed to be lower in sub-fertile testes than in normaltesticular tissue (Feng et al, Fertility and Sterility 71:85-89, 1999).C-kit signaling is also important for oogenesis and folliculogenesis(Parrott and Skinner, Endocrinology 140:4262-4271, 1999). These reportssuggest that modulation of c-kit enzymatic activity may be a method toreduce both male and female infertility.

While various groups have published on inhibitors of c-kit kinase,disclosing various chemical compounds, including2-phenylamino-imidazo[4,5-h]isoquinolin-9-ones (Snow, R J et al, J. Med.Chem. 2002, 45, 3394), pyrazolo[3,4-d]pyrimidines (Burchat, A F et al,Bioorganic and Med. Chem. Letters 2002, 12, 1987 and Hanke, J H et al,J. Biol. Chem. 1996, 271, 695), pyrrolo[2,3-d]pyrimidines (Altmann, E etal, Bioorganic and Med. Chem. Letters 2001, 11, 853),anilinoquinazolines (Wang, Y D et al, Bioorganic and Med. Chem. Letters2000, 10, 2477), imidazoquinoxalines (Chen, P. et al, Bioorganic andMed. Chem. Letters 2002, 12, 3153), PCT publication entitled, “Methodsof Modulating c-KIT Tyrosine Protein Kinase Function with IndolineCompounds” and PCT publication entitled, “Use of Tyrosine KinaseInhibitors for Treating Autoimmune Diseases”, none of these groupsdescribe the compounds of the present invention, and particularly asmodulators of kinase enzymes such as c-kit, and useful for theregulation of autoimmune disease(s), allergies, asthma, cancer and thelike.

BRIEF DESCRIPTION OF EXEMPLARY EMBODIMENTS OF THE INVENTION

The compounds of the present invention, including stereoisomers,tautomers, solvates, pharmaceutically acceptable salts and derivatives,and prodrugs thereof, are represented by general Formula I:

wherein A¹⁻³, R¹ and R³⁻⁶ are defined in the Detailed Descriptionsection hereinbelow.

The compounds of Formula I are capable of modulating the activity ofc-kit protein kinase and, therefore, are capable of regulating variousc-kit mediated disorders. More specifically, these compounds are usefulin the treatment, including preventative, prophylactic and therapeutictreatment, of c-kit kinase-associated or mediated disorders including,but not limited to, mast cell regulated autoimmune disorders andfibrotic disease. In one embodiment of the invention, the compounds ofFormula I are useful for the treatment of various c-kit mediateddiseases, including regulation of mast cell production, tumors relatedto mast cell proliferation and mastocytosis, allergic reactions andc-kit mediated fibrotic and autoimmune disease.

To treat patients for such disorders, another embodiment of theinvention provides a pharmaceutical composition comprising a compound ofFormula I and a pharmaceutically acceptable carrier. Such a compositioncan be administered to the subject, such as a human, for the purpose oftreating the disorder. Other therapeutic agents such as those describedbelow may be employed in combination with the inventive compounds, suchas in a combined composition, administered to the subject.Alternatively, such other therapeutic agent(s) may be administered priorto, simultaneously with, or following the administration of thecompound(s) of the present invention.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way.

DETAILED DESCRIPTION OF THE EXEMPLARY EMBODIMENTS OF THE INVENTION

In one embodiment, the present invention provides a compound of FormulaI

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt,derivative or prodrug thereof, wherein

one of A¹, A² and A³ is N and the other two of A¹, A² and A³ is CR²; oreach of A¹, A² and A³, independently, is CR²;

R¹ is —NR⁷R⁷, —NR⁷R⁸, —NR⁹R⁹, —C(O)NR⁷, —C(O)NR⁹, —NR²C(O)R⁷,—NR²C(O)R⁹, —NR²C(O)NR⁷, —NR²C(O)NR⁷, —S(O)₂NR⁷, —S(O)₂NR⁹ or—NR²S(O)₂NR⁷; or

R¹ is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹or a partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and optionally substituted independently with 1-5 substituents of R⁹;

alternatively, R¹ and A¹ taken together form a saturated or partially orfully unsaturated 5-6 membered ring of carbon atoms optionally including1-4 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-5 substituents of oxo, NR⁹R⁹, OR⁹, SR⁹,C(O)R⁹ or R⁹;

each R², independently, is H, halo, haloalkyl, NO₂, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, CN, OH, —O—C₁₋₈alkyl, —O-haloalkyl, SH,—S—C₁₋₁₈alkyl, NH₂, —NH—C₁₋₈alkyl, —N—(C₁₋₈alkyl)₂ or —C(O)—C₁₋₈alkyl,wherein the C₁₋₈alkyl, C₂₋₈alkenyl and C₂₋₈-alkynyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents of R⁹;

R³, at each occurrence, is H, halo, haloalkyl, NO₂, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, CN, OH, —O—C₁₋₈alkyl, —O-haloalkyl, SH,—S—C₁₋₈alkyl, NH₂, —NH—C₁₋₈alkyl, —N—(C₁₋₈alkyl)₂ or —C(O)—C₁₋₈alkyl,wherein the C₁₋₈alkyl, C₂₋₈-alkenyl and C₂₋₈-alkynyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents of R⁹;

R⁴ is H, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl or CN;

R⁵ is H, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl or CN;

R⁶ is C(O)R⁷, COOR⁷, C(O)NR⁷R⁷, C(O)NR⁷R⁸, S(O)₂R⁷, S(O)₂NR⁷R⁷,S(O)₂NR⁷R⁸, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl or C₂₋₁₀-alkynyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl and C₂₋₁₀-alkynyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of R⁸ or R⁹; or

R⁶ is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹or a partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and optionally substituted independently with 1-5 substituents of R⁹;

R⁷ is H, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₄-alkynyl, C₃₋₈-cycloalkyl orC₄₋₈-cycloalkenyl, each of the C₁₋₈-alkyl, C₂₋₄-alkenyl, C₂₋₈-alkynyl,C₃₋₈-cycloalkyl and C₄₋₈-cycloalkenyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸,OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸,NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹),OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹,NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹ or R⁹;

R⁸ is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-3 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹or a partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and optionally substituted independently with 1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-3 substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, —NHC(O)C₁₋₈-alkyl,C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl, C₁₋₈alkylamino-, C₁₋₈-dialkylamino-, C₁₋₈-alkoxyl,C₁₋₈-thioalkoxyl or a saturated or partially or fully unsaturated 5-8membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclicring system, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₈alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl, C₁₋₈-alkylamino-,C₁₋₈-dialkylamino-, C₁₋₈-alkoxyl, C₁₋₈-thioalkoxyl and ring of said ringsystem is optionally substituted independently with 1-3 substituents ofhalo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl,tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine,propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl orphenyl.

In another embodiment, the invention provides compounds wherein A¹ is Nand A² and A³, independently, are each CR², in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention provides compounds wherein A² is Nand A¹ and A³, independently, are each CR², in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention provides compounds wherein A³ is Nand A¹ and A², independently, are each CR², in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention provides compounds wherein each ofA¹, A² and A³, independently, are CR², in conjunction with any of theabove or below embodiments.

In another embodiment, the invention provides compounds wherein R¹ is—NR⁷R⁷, —NR⁷R⁸, —NR⁹R⁹, —C(O)NR⁷, —C(O)NR⁹, —NR²C(O)R⁷, —NR²C(O)R⁹,—NR²C(O)NR⁷, —NR²C(O)NR⁹, —S(O)₂NR⁷, —S(O)₂NR⁹ or —NR²S(O)₂NR⁷, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R¹ is—NR⁷R⁷, —NR⁷R⁸, —NR⁹R⁹, —C(O)NR⁷, —C(O)NR⁹, —NR²C(O)R⁷, —NR²C(O)R⁹,—S(O)₂NR⁷ or —S(O)₂NR⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds wherein R¹ is H,halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₈-alkyl, C₂₋₈-alkenyl,C₂₋₈-alkynyl, C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl, C₁₋₈alkylamino-,C₁₋₈-dialkylamino-, C₁₋₈alkoxyl or C₁₋₈-thioalkoxyl, in conjunction withany of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R¹ is apartially or fully saturated or unsaturated 3-8 membered monocyclic,6-12 membered bicyclic, or 7-14 membered tricyclic ring system, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, and wherein eachring of said ring system is optionally substituted independently with1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹ or a partially orfully saturated or unsaturated 5-6 membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R¹ isphenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, benzoxazolyl,benzothiazolyl, benzoxadiazolyl, indolyl, azaindolyl, isoindolyl,indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl or cyclohexyl, each of which isoptionally substituted independently with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R¹ isphenyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl, thiophenyl, furyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,oxazolyl, oxadiazolyl, isoxazolyl or isothiazolyl, each of which isoptionally substituted independently with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein each R²,independently, is H, F, Br, Cl, I, CF₃, CH₂CF₃, NO₂, C₁₋₈alkyl, CN, OH,—OCH₃, —OC₂H₅, —OCF₃, NH₂, —NH—C₁₋₆alkyl or —N—(C₁₋₈alkyl)₂, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein each R²,independently, is F, Br, Cl, I, CF₃, CN, OH, —OCH₃, —OCF₃, NH₂, methyl,ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamine, dimethylamine, ethylamine, diethylamine or propylamine, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R³ is H,C₁₋₈alkyl or CN, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds wherein R³ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R⁴ is H,C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl or CN, in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention provides compounds wherein R⁴ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R⁵ is H,C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl or CN, in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention provides compounds wherein R⁵ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R⁶ isC(O)R⁷, COOR⁷, C(O)NR⁷R⁷, C(O)NR⁷R⁸, S(O)₂R⁷, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl or C₂₋₁₀-alkynyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl and C₂₋₁₀-alkynyl optionally comprising 1-4 heteroatomsselected from N, O and S and optionally substituted with one or moresubstituents of R⁸ or R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds wherein R⁶ is apartially or fully saturated or unsaturated 3-8 membered monocyclic,6-12 membered bicyclic, or 7-14 membered tricyclic ring system, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, and wherein eachring of said ring system is optionally substituted independently with1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹ or a partially orfully saturated or unsaturated 5-6 membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R⁶ isphenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, benzoxazolyl,benzothiazolyl, benzoxadiazolyl, indolyl, azaindolyl, isoindolyl,indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl or cyclohexyl, each of which isoptionally substituted independently with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds wherein R⁶ isphenyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl, thiophenyl, furyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, pyrrolidinyl orpyrazolinyl, each of which is optionally substituted independently with1-5 substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds wherein R⁶ is aC₁₋₁₀-alkyl substituted with one of a phenyl, naphthyl, pyridyl,pyrimidinyl, triazinyl, pyridazinyl, thiophenyl, furyl, tetrahydrofuryl,pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinazolinyl,isoquinazolinyl, phthalazinyl, thieno-pyrazolyl, imidazolyl, triazolyl,thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl,isothiazolyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl, indolyl,azaindolyl, isoindolyl, indazolyl, benzofuranyl, dihydrobenzofuranyl,benzothiophenyl, benzimidazolyl, pyrrolidinyl, pyrazolinyl, morpholinyl,piperidinyl, piperazinyl, cyclopropyl, cyclobutyl, azetidinyl,cyclopentyl or a cyclohexyl ring, the ring optionally substituted with1-5 substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds wherein R⁹ isphenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, benzoxazolyl,benzothiazolyl, benzoxadiazolyl, indolyl, dihydroindolyl, azaindolyl,isoindolyl, indazolyl, benzofuranyl, dihydrobenzofuranyl,benzothiophenyl, benzimidazolyl, pyrrolidinyl, pyrazolinyl, morpholinyl,piperidinyl, piperazinyl, cyclopropyl, cyclobutyl, azetidinyl,cyclopentyl or cyclohexyl, each of which is optionally substitutedindependently with 1-5 substituents, as defined herein, in conjunctionwith any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula Iwherein

A¹ is N and each of A² and A³, independently, is CR²;

R¹ is —NR⁷R⁷, —NR⁷R⁸, —NR⁹R⁹, —C(O)NR⁷, —C(O)NR⁹, —NR²C(O)R⁷,—NR²C(O)R⁹, —NR²C(O)NR⁷, —NR²C(O)NR⁹, —S(O)₂NR⁷, —S(O)₂NR⁹ or—NR²S(O)₂NR⁷⁷;

each R², independently, is H, F, Br, Cl, I, CF₃, CH₂CF₃, NO₂, C₁₋₈alkyl,CN, OH, —OCH₃, —OC₂H₅, —OCF₃, NH₂, —NH—C₁₋₆alkyl or —N—(C₁₋₈alkyl)₂;

R³ and R⁴, at each occurrence, is H, C₁₋₈alkyl or CN; and

R⁶ is C₁₋₁₀-alkyl or C₂₋₁₀-alkenyl, each of which is optionallysubstituted with one or more substituents of R⁸ or R⁹; or

R⁶ is phenyl; naphthyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, benzoxazolyl,benzothiazolyl, benzoxadiazolyl, indolyl, azaindolyl, isoindolyl,indazolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl,benzimidazolyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl orcyclohexyl, each of which is optionally substituted independently with1-5 substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds defined byFormula II

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt,derivative or prodrug thereof, wherein

R¹ is —NR⁷R⁷, —NR⁷R⁸, —NR⁹R⁹, —C(O)NR⁷, —C(O)NR⁹, —NR²C(O)R⁷,—NR²C(O)R⁹, —NR²C(O)NR⁷, —NR²C(O)NR⁹, —S(O)₂NR⁷, —S(O)₂NR⁹ or—NR²S(O)₂NR⁷; or

R¹ is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹or a partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and optionally substituted independently with 1-5 substituents of R⁹;

each R², independently, is H, halo, haloalkyl, NO₂,C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, CN, OH, —O—C₁₋₈alkyl, —O-haloalkyl, SH,—S—C₁₋₈alkyl, NH₂, —NH—C₁₋₈alkyl, —N—(C₁₋₈alkyl)₂ or —C(O)—C₁₋₈alkyl,wherein the C₁₋₈-alkyl, C₂₋₈-alkenyl and C₂₋₈-alkynyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents of R⁹;

R³ is H, halo, haloalkyl, NO₂, C₁₋₈-alkyl, CN, OH, —O—C₁₋₈-alkyl,—O-haloalkyl, SH, —S—C₁₋₈alkyl, NH₂, —NH—C₁₋₈-alkyl or —N—(C₁₋₈alkyl)₂;

R⁵ is H, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl or CN;

R⁶ is C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl or C₂₋₁₀-alkynyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl and C₂₋₁₀-alkynyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of R⁸ or R⁹; or

R⁶ is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹or a partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and optionally substituted independently with 1-5 substituents of R⁹;

R⁷ is H, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl orC₄₋₈-cycloalkenyl, each of the C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₃₋₈-cycloalkyl and C₄₋₈-cycloalkenyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸,OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸,NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹),OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹,NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹ or R⁹;

R⁸ is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-3 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹or a partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and optionally substituted independently with 1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-3 substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₈-alkyl,C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl,C₁₋₈alkylamino-, C₁₋₈-dialkylamino-, C₁₋₈-alkoxyl, C₁₋₈-thioalkoxyl or asaturated or partially or fully unsaturated 5-8 membered monocyclic,6-12 membered bicyclic, or 7-14 membered tricyclic ring system, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₈alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl, C₁₋₈-alkylamino-, C₁₋₈-dialkylamino-, C₁₋₈-alkoxyl,C₁₋₈-thioalkoxyl and ring of said ring system is optionally substitutedindependently with 1-3 substituents of halo, haloalkyl, CN, NO₂, NH₂,OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine,ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the invention provides compounds of Formula IIwherein

R³ is halo, haloalkyl, C₁₋₈alkyl, CN, OH, —O—C₁₋₈alkyl, —O-haloalkyl,—NH—C₁₋₈alkyl or —N—(C₁₋₈alkyl)₂;

R⁵ is H; and

R⁶ is C₁₋₁₀-alkyl or C₂₋₁₀-alkenyl, each of which is optionallysubstituted with one or more substituents of R⁸ or R⁹; or

R⁶ is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, benzoxazolyl,benzothiazolyl, benzoxadiazolyl, indolyl, azaindolyl, isoindolyl,indazolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl,benzimidazolyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl orcyclohexyl, each of which is optionally substituted independently with1-5 substituents of R⁹, in conjunction with any of the above or belowembodiments.

In many further embodiments of compounds related to Formula II, R¹, R²,R³, R⁵ and R⁶ are as defined in any of the above embodiments inconjunction with compounds of Formula I hereinabove.

In yet another embodiment, there are provided the compounds of Examples4 and 6-11 described herein, or a pharmaceutically acceptable saltthereof.

The compounds of Formulas I or II, and stereoisomers, solvates,tautomers, pharmaceutically acceptable salts and derivatives, andprodrugs of these compounds, are useful for treating subjects, typicallymammals such as humans, with various conditions and/or disease states,as previously described. To this end, and in another embodiment, theinvention provides pharmaceutical compositions (also commonly referredto as medicaments, which may be used to treat various conditions ordiseases) comprising one or more of the compounds of Formula I or II,including compounds according to any of the various embodimentsdescribed above, and a pharmaceutically acceptable carrier or diluent.

The compounds of Formula I or II, or pharmaceutical compositioncomprising such compound(s), may be administered in an effective amountto the subject to modulate one or more target proteins in the subjectthereby treating the target-mediated disease or condition. Accordingly,another embodiment of the invention relates to a method for treating ac-kit kinase-mediated disorder in a mammal, comprising administering tothe mammal a therapeutically effective amount of a compound according toany one of the above embodiments.

Further embodiments of the present invention include methods fortreating conditions, disorders or diseases related to c-kit, includingwithout limitation, treating the over-production of histamine in asubject, treating an autoimmune disease, mastocytosis, mast cell tumors,asthma, severe asthma, chronic rhinitis, allergy associated chrinicrhinitis, small cell lung cancer, acute myelocytic leukemia, acutelymphocytic leukemia, myelodysplastic syndrome, chronic myelogenusleukemia, colorectal carcinoma, gastric carcinoma, gastrointestinalstromal tumor, testicular cancer, glioblstoma, astrocytoma, fibroticdiseases including without limitation, idiopathic pulmonary fibrosis, ora combination thereof in a subject, wherein each of the above methods,independently, comprise administering to the subject or mammal atherapeutically effective amount, or a therapeutically effective dosageamount, of a compound according to any one of the above embodimentsrelated to Formulas I or II.

Various other embodiments of the invention relate to the manufactureand/or use of a medicament, comprising a compound of Formulas I or II,for the purposes of treating the subject therewith, as described herein.For example, and in another embodiment, the invention relates to themanufacture of, or use of, a medicament comprising a compound accordingto any one of the above embodiments related to Formulas I or II for thetreatment of fibrotic disease.

Another embodiment of the invention relates to a method of making acompound according to Formula I or II, as described herein, comprisingthe step of reacting a compound of Formula 4

wherein R³, R⁴, R⁵ and R⁶ are as defined herein, with a compound havinga general Formula 5

, wherein A¹, A², A³ and R¹ are as defined herein, in the presence ofCuI and palladium to make a compound of Formula I.

Meanings and Definitions

Unless otherwise specified, the following terms found in thespecification and claims have the following meanings and/or definitions:aq: Aqueous BSA: Bovine Serum Albumin DCE: Dichloroethane DCM:Dichloromethane DIEA: Diisopropylethylamine DMF: N,N-DimethylformamideDMSO: Dimethylsulfoxide EDTA: Ethylene diamine tetraacetic acid EtOAc:Ethyl acetate EtOH: Ethanol g: Gram(s) h: Hour(s) HBTU:O-Benzotriazol-1-yl-N,N,N′,N′- tetramethyluronium hexafluorophosphateHepes: N-[2-Hydroxyethyl]piperazine-N′- [2-ethanesulfonic acid] IC₅₀value: The concentration of an inhibitor that causes a 50% reduction ina measured activity. IPA isopropyl alcohol MeI: Methyl iodide MeCN:Acetonitrile MeOH: Methanol min: Minute(s) mmol: Millimole(s) NCS:N-chlorosuccinimide NMP: N-methylpyrrolidone RT: Room temperature TFA:Trifluoroacetic acid THF: Tetrahydrofuran

Generally, reference to a certain element such as hydrogen or H is meantto include all isotopes of that element. For example, if an R group isdefined to include hydrogen or H, it may also include deuterium andtritium. Compounds comprising radioisotopes such as tritium, C¹⁴, P³²and S³⁵ are thus within the scope of the invention. Procedures forinserting such labels into the compounds of the invention will bereadily apparent to those skilled in the art based on the disclosureherein.

The term “substituted” as used herein refers to a group, such as thosedefined below, in which one or more bonds to a hydrogen atom containedtherein are replaced by a bond to non-hydrogen or non-carbon atomsincluding, but not limited to, a halogen atom such as F, Cl, Br, and I;an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxygroups, and ester groups; a sulfur atom in groups such as thiol groups,alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, andsulfonyl groups such as sulfonyl halides and sulfonomides; a nitrogenatom in groups such as amines, amides, alkylamines, dialkylamines,arylamines, alkylarylamines, diarylamines, N-oxides, ureas, imines,imides, and enamines; a silicon atom in groups such as in trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, andtriarylsilyl groups; and other heteroatoms in various other groups.Substituted alkyl groups and also substituted cycloalkyl groups andothers also include groups in which one or more bonds to a carbon(s) orhydrogen(s) atom is replaced by a bond to a heteroatom such as oxygen incarboxylic acid, ester and carbamate groups; and nitrogen in groups suchas imines, oximes, hydrazones, and nitriles.

Substituents, including alkyl and ring groups, may be either monovalentor polyvalent depending on the context of their usage. For example, ifdescription contained the group R¹-R²-R³ and R² was defined asC₁₋₆alkyl, then the R² alkyl would be considered polyvalent because itmust be bonded to at least R¹ and R³. Alternatively, if R¹ were definedas C₁₋₆alkyl, then the R¹ alkyl would be monovalent (except any furthersubstitution language).

The term “unsubstituted” as used herein with reference to a group, meansthat the group does not have one or more bonds to a hydrogen or carbonatom contained therein replaced by a bond to non-hydrogen or non-carbonatom, as described above.

The term “optionally substituted” as used herein with reference to agroup, means that the group may be substituted with a specified numberof defined substituents or the group may remain unsubstituted.Generally, the scope of the contemplated substitutions of a particulargroup will be specified.

The term “alkyl” as used herein either alone or within other terms suchas “haloalkyl”, “alkylamino” and “cycloalkyl”, refers to linear,branched or cyclic radicals having one to about twelve carbon atoms.“Cycloalkyl” is also used exclusively herein to refer specifically tofully or partially saturated cyclic alkyl radicals. Examples of “alkyl”radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, cyclopropyl, cyclopentyl,cyclohexyl and the like.

The term C_(a-b)alkyl” as used herein refers to an alkyl groupcomprising from a to b carbon atoms in a branched, cyclical or linearrelationship or any combination of the three. The alkyl groups describedin this section may also contain double or triple bonds. Examples ofC₁₋₈alkyl include, but are not limited to the following:

The term “halogen” and “halo” as used herein, refers to a halogen atomsselected from F, Cl, Br and I.

The term “haloalkyl”, as used herein refers to radicals wherein any oneor more of the alkyl carbon atoms is substituted with halo as definedabove.

Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals including perhaloalkyl. A monohaloalkyl radical, for oneexample, may have an iodo, bromo, chloro or fluoro atom within theradical. Dihalo and polyhaloalkyl radicals may have two or more of thesame halo atoms or a combination of different halo radicals. Examples ofhaloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. The term “perfluoroalkyl” means alkyl radicals havingall hydrogen atoms replaced with fluoro atoms. Examples includetrifluoromethyl and pentafluoroethyl.

The term “C_(a-b)haloalkyl” as used herein refers to an alkyl group, asdescribed above, wherein any number, and at least one, of the hydrogenatoms attached to the alkyl chain are replaced by F, Cl, Br or I.Examples of haloalkyl includes, without limitation, trifluoromethyl,pentafluoroethyl and the like.

The term “hydroxyalkyl” as used herein refers to linear or branchedalkyl radicals having one to about ten carbon atoms any one of which maybe substituted with one or more hydroxyl radicals. Examples of suchradicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl and hydroxyhexyl.

The term “alkoxy” as used herein refers to linear or branchedoxy-containing radicals each having alkyl portions of one to about tencarbon atoms.

Examples of such radicals include methoxy, ethoxy, propoxy, butoxy andtert-butoxy. Alkoxy radicals may be further substituted with one or morehalo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy”radicals. Examples of lower haloalkoxy radicals having one to threecarbon atoms include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term “sulfonyl”, as used herein whether alone or linked to otherterms such as alkylsulfonyl, refers respectively to divalent radicals—SO₂—.

The term “amino”, as used herein whether alone or linked to other terms,refers to a nitrogen radical containing two hydrogen atoms (NH₂), anitrogen radical which is mono-substituted such as an alkylamine(methylamine for example), or a nitrogen radical which is disubstitutedsuch as a dialkylamine (dimethylamine for example). Generally, the aminenitrogen is the point of attachment to the group in question.Accordingly, the term “alkylamino” or dialkylamino” as used herein,means a mono-alkyl or bis-alkyl substituted amine-linked group. The term“cycloalkylamino” refers to an amine-linked cycloalkyl group. The term“arylamino” refers to an amine-linked aryl group. The term“heteroarylamino” refers to an amine-linked heteroaryl group. The term“heterocyclylamino” refers to an amino-linked heterocyclyl group.

The phrase “partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S” asused herein, means each ring of the single, double or triple ringradical or ring system (fused ring radical in the case of a double ortriple) may be a carbocyclic ring (“cycloalkyl”), an aromatic carbocycle(an “aryl” group), a heterocyclic ring or a heteroaromatic ring (a“heteroaryl” ring), each of which is optionally substituted asspecified.

The term “aryl”, as used herein alone or in combination, refers to acarbocyclic aromatic system containing one, two or three rings whereinsuch rings may be attached together in a fused manner. The term “aryl”includes, without limitation, aromatic radicals such as phenyl,naphthyl, indenyl, tetrahydronaphthyl, and indanyl. The “aryl” group mayhave 1 to 3 substituents such as alkyl, hydroxyl, halo, haloalkyl,nitro, cyano, alkoxy and alkylamino. “Aryl” also includes the moietywherein the aromatic carbocycle is fused with a C₃₋₆cycloalkyl bridge,wherein the bridge optionally includes 1, 2 or 3 heteroatoms selectedfrom N, O and S. For example, phenyl substituted with —O—CH₂—O— formsthe aryl benzodioxolyl substituent.

The term “heterocyclic” as used herein, refers to fully or partiallysaturated heteroatom-containing ring radicals, where the heteroatom(s)may be selected from nitrogen, sulfur and oxygen.

The term “heterocycloalkyl” as used herein, refers to saturated andpartially saturated (or partially unsaturated) heteroatom-containingring radicals, where the heteroatoms may be selected from nitrogen,sulfur and oxygen. It does not include rings containing —O—O—, —O—S— or—S—S— portions. Said “heterocycloalkyl” group may have 1 to 3substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl,oxo, alkoxy, amino and alkylamino.

Examples of saturated heterocycloalkyl radicals include saturated 3 to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

The term “heteroaryl” as used herein, refers fully unsaturatedheteroatom-containing ring radicals, where the heteroatoms may beselected from nitrogen, sulfur and oxygen. Examples of heteroarylradicals, include unsaturated 5 to 6 membered heteromonocyclyl groupcontaining 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic groupcontaining an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl[e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl];unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl].

The term “heteroaryl” also embraces radicals where heterocyclic radicalsare fused/condensed with aryl radicals (also referred to herein as“arylheterocycloalkyl”): unsaturated condensed heterocyclic groupcontaining 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Preferredheterocyclic radicals include five to ten membered fused or unfusedradicals. More preferred examples of heteroaryl radicals includequinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl,oxazolyl, furyl, and pyrazinyl. Other preferred heteroaryl radicals are5- or 6-membered heteroaryl, containing one or two heteroatoms selectedfrom sulfur, nitrogen and oxygen, selected from thienyl, furyl,pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.

Further examples of suitable heterocycles and heteroaryls, some of whichhave been described above, include, without limitation, the following:

“Saturated or unsaturated” means a moiety or substituent that iscompletely saturated, completely unsaturated, or has any degree ofunsaturation therein. Examples of a saturated or unsaturated 6-memberedring carbocycle would include phenyl, cyclohexyl, cyclohexenyl andcyclohexadienyl.

The term “salt” refers to a salt form of a free base compound of thepresent invention, as appreciated by persons of ordinary skill in theart. Salts may be prepared by conventional means, known to those skilledin the art. The term “pharmaceutically-acceptable”, when used inreference to a salt, refers to salt forms of a given compound, which arewithin governmental regulatory safety guidelines for ingestion and/oradministration to a subject. The term “pharmaceutically-acceptablesalts” embraces salts commonly used to form alkali metal salts and toform addition salts of free acids or free bases. The nature of the saltis not critical, provided that it is safe and consideredpharmaceutically-acceptable.

Suitable pharmaceutically-acceptable acid addition salts of compounds ofFormulas I-II may be prepared from an inorganic acid or from an organicacid.

Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriateorganic acids may be selected from aliphatic, cycloaliphatic, aromatic,arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organicacids, example of which are formic, acetic, adipic, butyric, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic,β-hydroxybutyric, salicylic, galactaric and galacturonic acid.

Suitable pharmaceutically-acceptable base addition salts of compounds ofFormulas I-II include metallic salts, such as salts made from aluminum,calcium, lithium, magnesium, potassium, sodium and zinc, or salts madefrom organic bases including primary, secondary and tertiary amines,substituted amines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, trimethylamine.

Additional examples of such acid and base addition salts can be found inBerge et al., J. Pharm. Sci., 66, 1 (1977). All of these salts may beprepared by conventional means from the corresponding compound of theinvention by reacting, for example, the appropriate acid or base withthe compound of Formulas I-II.

Also, the basic nitrogen-containing groups of compounds of Formulas I-IIcan be quaternized with such agents as lower alkyl halides including,without limitation, methyl, ethyl, propyl, and butyl chloride, bromidesand iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl, anddiamyl sulfates, long chain halides such as decyl, lauryl, myristyl andstearyl chlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl bromides, and others. Water or oil-soluble or dispersibleproducts may be obtained by quaternizing such basic nitrogen groups incompounds of Formulas I-II.

The term “derivative” as used herein, refers to simple modifications,readily apparent to those of ordinary skill in the art, on the parentcore structure of Formulas I or II, which does not significantly affect(generally decrease) the activity of the compound in-vitro as well as invivo, in a subject. The term, “derivative” as used herein, iscontemplated to include pharmaceutically acceptable derivatives ofcompounds of Formulas I or II.

The term “pharmaceutically acceptable” when used with reference to aderivative, is consistent in meaning with reference to a salt, andrefers to a derivative that is pharmacologically safe for consumption,generally as determined by a governmental or authorized regulatory body.

The term “leaving group” as used herein, refers to groups readilydisplaceable by a nucleophile, such as an amine, a thiol or an alcoholnucleophile. Leaving groups are well known in the art. Examples ofleaving groups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.

The term “protecting group” as used herein, refers to groups well knownin the art which are used to prevent selected reactive groups, such ascarboxy, amino, hydroxy, mercapto and the like, from undergoingundesired reactions, such as nucleophilic, electrophilic, oxidation,reduction and the like. Preferred protecting groups are indicated hereinwhere appropriate. Examples of amino protecting groups include, but arenot limited to, aralkyl (also known as arylalkyl), substituted aralkyl,cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substitutedallyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like.Examples of aralkyl include, but are not limited to, benzyl,ortho-methylbenzyl, trityl and benzhydryl, which can be optionallysubstituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyland the like, and salts, such as phosphonium and ammonium salts.Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl,9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like. Examples ofcycloalkenylalkyl or substituted cycloalkylenylalkyl radicals,preferably have 6-10 carbon atoms, include, but are not limited to,cyclohexenyl methyl and the like. Suitable acyl, alkoxycarbonyl andaralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl,iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl,tri-fluoroacetyl, tri-chloro acetyl, phthaloyl and the like. A mixtureof protecting groups can be used to protect the same amino group, suchas a primary amino group can be protected by both an aralkyl group andan aralkoxycarbonyl group. Amino protecting groups can also form aheterocyclic ring with the nitrogen to which they are attached, forexample, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl,maleimidyl and the like and where these heterocyclic groups can furtherinclude adjoining aryl and cycloalkyl rings. In addition, theheterocyclic groups can be mono-, di- or tri-substituted, such asnitrophthalimidyl. Amino groups may also be protected against undesiredreactions, such as oxidation, through the formation of an addition salt,such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid andthe like. Many of the amino protecting groups, including aralkyl groupsfor example, are also suitable for protecting carboxy, hydroxy andmercapto groups. Alkyl groups are also suitable groups for protectinghydroxy and mercapto groups, such as tert-butyl.

Silyl protecting groups are groups containing silicon atoms which areoptionally substituted by one or more alkyl, aryl and aralkyl groups.Suitable silyl protecting groups include, but are not limited to,trimethylsilyl, triethylsilyl, tri-isopropylsilyl,tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyi. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-tri-silyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium fluoride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydrolysis and hydrogenolysis conditions well known tothose skilled in the art.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as cyclic and acyclic amidineand guanidine groups, heteroatom substituted heteroaryl groups (Y′═O, S,NR), and the like, which are illustrated in the following examples:

and though one form is named, described, displayed and/or claimedherein, all the tautomeric forms are intended to be inherently includedin such name, description, display and/or claim.

Prodrugs of the compounds of this invention are also contemplated bythis invention. The term “prodrug”, as used herein, refers to acompound, which when administered to the body of a subject (such as amammal), breaks down in the subject's metabolic pathway to provide anactive compound of Formulas I or II. More specifically, a prodrug is anactive or inactive “masked” compound that is modified chemically throughin vivo physiological action, such as hydrolysis, metabolism and thelike, into a compound of this invention following administration of theprodrug to a subject or patient. The suitability and techniques involvedin making and using prodrugs are well known by those skilled in the art.For a general discussion of prodrugs involving esters see Svensson andTunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design ofProdrugs, Elsevier (1985).

One common form of a prodrug is a masked carboxylic acid group. Examplesof a masked carboxylate anion include a variety of esters, such as alkyl(for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),aralkyl (for example, benzyl, p-methoxybenzyl), andalkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have beenmasked as arylcarbonyloxymethyl substituted derivatives which arecleaved by esterases in vivo releasing the free drug and formaldehyde(Bundgaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidicNH group, such as imidazole, imide, indole and the like, have beenmasked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs,Elsevier (1985)). Hydroxy groups have been masked as phosphates, estersand ethers. EP 039,051 (Sloan and Little, Apr. 11, 1981) disclosesMannich-base hydroxamic acid prodrugs, their preparation and use.

Steroeisomers of the compounds of the present invention are alsocontemplated herein. The term “stereoisomer” as used herein refers to acompound having one or more asymmetric centers. Chiral centers in acompound generally cause that compound to exist in many differentconformations or stereoisomers. The term “stereoisomers” includesenantiomers, diastereomers, atropisomers and geometric isomers.Stereoisomers generally possess different chemical properties and/orbiological activity, as appreciated by those skilled in the art. Forexample, one stereoisomer may be more active and/or may exhibitbeneficial effects in comparison to other stereoisomer(s) or whenseparated from the other stereoisomer(s). However, it is well within theskill of the ordinary artisan to separate, and/or to selectively preparesaid stereoisomers. Accordingly, “stereoisomers” of the presentinvention necessarily include mixtures of stereoisomers, includingracemic mixtures, individual stereoisomers, and optically active forms.

The term “solvate” when used with reference to a compound refers to acompound, which is associated with one or more molecules of a solvent,such as an organic solvent, inorganic solvent, aqueous solvent ormixtures thereof. The compounds of Formulas I or II may also besolvated, especially hydrated. Hydration may occur during manufacturingof the compounds or compositions comprising the compounds, or thehydration may occur over time due to the hygroscopic nature of thecompounds. Compounds of the invention may exist as organic solvates aswell, including DMF, ether, and alcohol solvates among others. Theidentification and preparation of any particular solvate is within theskill of the ordinary artisan of synthetic organic or medicinalchemistry.

The term “treatment” as used herein, includes therapeutic treatment aswell as prophylactic treatment (either preventing the onset of disordersaltogether or delaying the onset of a pre-clinically evident stage ofdisorders in individuals).

The term “therapeutically-effective” as used herein, is intended toqualify the amount of each compound of Formulas I or II, which willachieve the goal of treatment, for example, improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies.

The term “C-kit-mediated disease or disease states” refer to all diseasestates wherein C-kit plays a role, either directly as C-kit itself, orby C-kit inducing or mediating other proteins, cytokines, enzymes ordisease-causing agents and the like to be released, activated orotherwise directly or indirectly regulated. The specification and claimscontain a listing of species using the language “selected from . . . and. . . ” and “is . . . or . . . ” (sometimes referred to as Markushgroups). When this language is used in this application, unlessotherwise stated it is meant to include the group as a whole, or anysingle members thereof, or any subgroups thereof. The use of thislanguage is merely for shorthand purposes and is not meant in any way tolimit the removal of individual elements or subgroups from the genus.

Synthesis

Compounds of Formula I and II can be synthesized according to one ormore of the following schematic procedures and specific methods whereinthe substituents are as defined for Formulas I and II, above, exceptwhere further noted. The procedures and methods as shown relate topreparation of compounds having unspecified stereochemistry. However,such procedures and methods may generally be applicable to thosecompounds of a specific stereochemistry, e.g., where the stereochemistryabout a group is (S) or (R). In addition, the compounds having onestereochemistry (e.g., (R)) can often be utilized to produce thosehaving opposite stereochemistry (i.e., (S)) using well-known methods,for example, by inversion.

Scheme 1 describes a general method for preparingheteroaryl-alkyne-substituted pyridone compounds 6 and 6′, of Formulas Iand II. As shown, a desirable chloro, bromo-substituted pyridine 1 canbe treated with aqueous formic acid, under suitable conditions toprovide the corresponding bromo-pyridone intermediate 2. The aminonitrogen of amide 2 may be reacted with an iodo-compound 3, such as anaryl-iodide compound 3′ as shown, under cuprate reaction conditionsusing a copper species, such as copper iodide, and a suitable base, inthe presence of a suitable solvent to generate the correspondingR6-couple dadduct 4 or 4′. The iodide of compounds 4 and 4′ may bereacted with heteroaryl alkynes 5 in the presence of a copper species,such as copper iodide, and a palladium species as shown, to afford thecorresponding coupled adducts 6 and 6′.

Scheme 2 describes how alkynes 5 may be made from desirableR¹-substituted heteroaryl compounds 7 for coupling to a pyridonecompound 4 or 4′ (scheme 1 above), of Formulas I and II. As shown, adesirable iodo-substituted heteroaryl compound 7 can be treated withTMS-protected acetylene, in the presence of copper and palladium, toprovide the corresponding TMS-acetylide intermediate (not shown), whichcan be reacted with a suitable base, such as potassium carbonate, tocleave the trimethyl silyl (TMS) protecting group and free the acetylenefunctional group to yield compound 5. Compound 5 may be reacted withdesired bromo-pyridones 4 and 4′, as shown in scheme 1 above.

The specific examples described in detail below further exemplify thesynthesis of compounds of Formulas I and II, generally described inSchemes 1 and 2 above.

Analytical Methods:

Unless otherwise indicated all HPLC analyses were run on an HP-1000 orHP-1050 system with an HP Zorbax SB-C₁₈ (5μ) reverse phase column(4.6×150 mm) run at 30° C. with a flow rate of 1.00 mL/min. The mobilephase used solvent A (H₂O/0.1% TFA) and solvent B (CH₃CN/0.1% TFA) witha 20 min gradient from 10% to 90% CH₃CN. The gradient was followed by a2 min return to 10% CH₃CN and a 3 min flush.

LC-MS Methods:

Unless otherwise noted, the LC-MS analysis of exemplary compounds,intermediates and starting materials described here were conducted usingone or both of the following two methods:

Method A:

Samples were run on an HP-1100 system with an HP Zorbax SB-C₈ (5μ)reverse phase column (4.6×50 mm) run at 30° C. with a flow rate of 0.75mL/min. The mobile phase used solvent A (H₂O/0.1% HCO₂H) and solvent B(CH₃CN/0.1% HCO₂H) with a 10 min gradient from 10% to 90% CH₃CN. Thegradient was followed by a 1 min return to 10% CH₃CN and a 2 min flush.

Method B:

Samples were run on an HP-1100 system with an HP Zorbax SB-C₈ (5μ)reverse phase column (4.6×50 mm) run at 30° C. with a flow rate of 1.5mL/min. The mobile phase used solvent A (H₂O/0.1% HCO₂H) and solvent B(CH₃CN/0.1% HCO₂H) with a 5 min gradient from 10% to 90% CH₃CN. Thegradient was followed by a 0.5 min return to 10% CH₃CN and a 1.5 minflush.

Example 1

Synthesis of 3-bromo-4-methylpyridin-2(1H)-one

To a resealable pressure vessel charged with 3-bromo-2-chloro-4-picoline(1.200 g, 5.81 mmol) was added formic acid (13.1 ml, 348 mmol) and H₂O(4.00 ml, 222 mmol). The tube was sealed and the solution heated to 120°C. After 72 hrs, the solution was cooled to RT and concentrated invacuo. The residue was purified by reverse phase chromatography(neutral) to afford 3-bromo-4-methylpyridin-2(1H)-one as a white solid.MH+=188.0.

Example 2

Synthesis of3-iodo-4-methyl-1-(3-(trifluoromethoxy)phenyl)pyridin-2(1H)-one

A resealable pressure vessel was charged with copper (I) iodide (0.081g, 0.425 mmol), 1-iodo-3-(trifluoromethoxy)benzene (0.434 ml, 2.77 mmol)and 3-bromo-4-methylpyridin-2(1H)-one (0.400 g, 2.13 mmol). To themixture was added dioxane (3 mL) followed byN¹,N²-dimethylethane-1,2-diamine (0.092 ml, 0.851 mmol). The vessel waspurged with argon, sealed, and heated to 110° C. for 24 hrs. The mixturewas cooled to RT, diluted with EtOAc and washed with water and brine.The organic fraction was adsorbed onto silica gel and purified by silicagel chromatography using 15-80% Hexanes:EtOAc to afford3-iodo-4-methyl-1-(3-(trifluoromethoxy)phenyl)pyridin-2(1H)-one as anoff-white solid. MH+=396.0.

Example 3

Synthesis of 5-ethynylpyrimidin-2-amine

A flask was charged with 5-iodopyrimidin-2-amine (25.0 g, 110 mmol),acetonitrile (900 ml, 110 mmol), trimethylsilylacetylene (35 ml, 241mmol), triethylamine (93 ml, 658 mmol), Pd(PPh3)₄Cl2 (3.9 g, 5.5 mmol)and finally copper(I) iodide (1.1 g, 5.5 mmol). The flask was put undervacuum then filled with argon and stirred at RT overnight using amechanical stirrer. The solvent was removed under vacuum, the residuetaken up in methanol (600 ml) and potassium carbonate (152 g, 1097 mmol)was added. The mixture was stirred at RT using mechanical stirring for 2hrs. Activated carbon (˜50 mL) was added to the reaction and stirringcontinued for 15 min. The reaction mixture was then filtered through aplug of celite and the filtrate was concentrated to a volume of ˜400 mLand the precipitate was filtered. The filtrate was concentrated down toa thick paste which was slurried in ˜150 mL of 10% MeOH/H₂O for 20 minat RT. The solids were then filtered off to afford5-ethynylpyrimidin-2-amine.

Example 4

Synthesis of3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-1-(3-(trifluoromethyl)phenyl)-2(1H)-pyridinone

To a mixture of 5-ethynylpyrimidin-2-amine (0.023 g, 0.19 mmol),3-iodo-4-methyl-1-(3-(trifluoromethyl)phenyl)pyridin-2(1H)-one (0.041 g,0.11 mmol), copper(I) iodide (0.001 g, 0.0054 mmol), and Pd(PPh₃)₂Cl₂(0.004 g, 0.0054 mmol) was added MeCN (2 mL) and triethylamine (0.300ml, 2.200 mmol). The mixture was heated to 80° C. in a resealable tube.After 16 hrs, the reaction mixture was diluted with EtOAc and washedwith water and brine. After concentrating in vacuo, the crude residuewas purified by silica gel chromatography using 30-100% hexanes:EtOAc toafford3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-1-(3-(trifluoromethyl)phenyl)-2(1H)-pyridinoneas a white solid. Found M+H+=371.2.

Example 5

Synthesis of 1-(6-iodo-3,3-dimethylindolin-1-yl)ethanone

To a suspension of 1-(6-amino-3,3-dimethylindolin-1-yl)ethanone (2.000g, 9.791 mmol) in concentrated HCl (20.00 ml, 548.5 mmol) at 0° C. wasadded ice (15 g) followed by a solution of sodium nitrite (0.7769 g,11.26 mmol) in water (15 mL). After 45 min, a solution of potassiumiodide (3.251 g, 19.58 mmol) in water (15 mL) was added dropwise. After5 min, the mixture was allowed to warm to RT. After 1 hr, CH₂Cl₂ (ca.100 mL) and water (ca. 25 mL) were added. The aqueous fraction wasextracted 2× with DCM. The combined organic fractions were washed withsaturated NaHCO₃ followed by 10% NaS₂O₃ and brine. After drying withNa₂SO₄, the deep red solution was concentrated in vacuo and purified bysilica gel chromatography using 10-60% hexanes:EtOAc to afford1-(6-iodo-3,3-dimethylindolin-1-yl)ethanone as an orange oil thatsolidified upon standing.

Found M+H+=316.0.

Example 6

Synthesis of3-((2-amino-5-pyrimidinyl)ethynyl)-1-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-4-methyl-2(1H)-pyridinone

A mixture of1-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-2(1H)-pyridinone(0.103 g, 0.25 mmol) and sodium tert-butoxide (0.072 g, 0.75 mmol) intBuOH (4 mL) was heated under microwave radiation at 100° C. for 10 min.The reaction mixture was diluted with EtOAc and washed with saturatedNH₄Cl and brine. The solids formed were filtered and recombined with theorganic fraction. After concentrating the organic fraction in vacuo, theresidue was purified by silica gel chromatography using 0-10% MeOH inEtOAc to afford3-((2-amino-5-pyrimidinyl)ethynyl)-1-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-4-methyl-2(1H)-pyridinoneas a light yellow solid. Found M+H+=372.3.

The following compounds, Examples 7-11, were made using proceduressimilar to those described in Examples 1-6. Ex. No M + H Compound Name 7331.1 3-((2-amino-5-pyrimidinyl)ethynyl)-1-(3,4-dimethylphenyl)-4-methyl-2(1H)-pyridinone 8 414.11-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-2(1H)- pyridinone 9 345.13-((2-amino-5-pyrimidinyl)ethynyl)-1-(2,3-dihydro-1-benzofuran-5-yl)-4-methyl-2(1H)-pyridinone 10 387.13-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-1-(3-((trifluoromethyl)oxy)phenyl)-2(1H)-pyridinone 11 355.14-methyl-3-(3-pyridinylethynyl)-1-(3-(trifluoromethyl)phenyl)-2(1H)-pyridinone

The following compounds in Tables 1 and 2 are additional representativeexamples of compounds of Formula I, as provided by the presentinvention. TABLE 1

Ex. No. R¹ R³ R⁶ 12 H Methyl or 2-CH₃-phenyl chloro 13 NH₂ Methyl or4-CF₃-phenyl chloro 14 1-piperidinyl Methyl or 3-CF₃-phenyl chloro 15cyclohexyl-N- Methyl or 6-CH₃-phenyl chloro 16 morpholine-(CH₂)₂—N—Methyl or 2-OCH₃-phenyl chloro 17 (CH₃)₂N—(CH₂)₂—N— Methyl or4-OCH₃-phenyl chloro 18 (C₂H₅)₂N—(CH₂)₂—N— Methyl or pyridine chloro 193-OH-1-pyrrolidinyl Methyl or indole chloro 20 3-amido-1-pyrrolidinylMethyl or indoline chloro 21 4-amido-1-piperidinyl Methyl or benzofuranchloro 22 3-amido-1-piperidinyl Methyl or 2-F-phenyl chloro 234N-CH₃-1-piperizinyl Methyl or 4-F-phenyl chloro 24 H Methyl orDihydrobenzofuran chloro 25 NH₂ Methyl or cyclohexyl-(CH₂)₂— cyclopropyl26 4-CH₃-phenyl Methyl or cyclopropyl-(CH₂)₂— cyclopropyl 27 H Methyl or2-CH₃-phenyl cyclopropyl 28 NH₂ Methyl or 4-CF₃-phenyl cyclopropyl 29 HMethyl or 3-CF₃-phenyl cyclopropyl 30 NH₂ Methyl or 6-CH₃-phenylcyclopropyl 31 3-thiophene Methyl or 2-OCH₃-phenyl cyclopropyl 32 HMethyl or 4-OCH₃-phenyl cyclopropyl 33 NH₂ Methyl or pyridinecyclopropyl 34 1-piperazinyl Methyl or indole cyclopropyl 351-piperidinyl Methyl or indoline cyclopropyl 36 cyclohexyl-N- Methyl orbenzofuran cyclopropyl 37 morpoline-(CH₂)₂—N— Methyl or 2-F-phenylcyclopropyl 38 (CH₃)₂N—(CH₂)₂—N— Methyl or 4-F-phenyl cyclopropyl 39(C₂H₅)₂N—(CH₂)₂—N— Methyl or dihydrobenzofuran cyclopropyl 40 H Methylor 2-CH₃-phenyl cyclopropyl 41 NH₂ Methyl or 4-CF₃-phenyl cyclopropyl 423-amido-1-piperidinyl Methyl or 3-CF₃-phenyl cyclopropyl 424-amido-1-piperidinyl Methyl or 6-CH₃-phenyl cyclopropyl 43 H Methyl or2-OCH₃-phenyl cyclopropyl 44 NH₂ Methyl or 4-OCH₃-phenyl cyclopropyl 45H Methyl or pyridine cyclopropyl 46 NH₂ Methyl or indole cyclopropyl 47H Methyl or indoline cyclopropyl 48 NH₂ Methyl or benzofuran cyclopropyl49 H Methyl or 2-F-phenyl cyclopropyl 50 NH₂ Methyl or 4-F-phenylcyclopropyl 51 H Methyl or dihydrobenzofuran cyclopropyl 52 NH₂ Methylor cyclohexyl-(CH₂)₂— cyclopropyl 53 1-morpholinyl Methyl orcyclopropyl-(CH₂)₂— cyclopropyl 54 H Methyl or 2-CH₃-phenyl cyclopropyl55 NH₂ Methyl or 4-CF₃-phenyl cyclopropyl 56 H Methyl or 3-CF₃-phenylcyclopropyl 57 NH₂ Methyl or 6-CH₃-phenyl cyclopropyl 58 H Methyl or2-OCH₃-phenyl cyclopropyl 59 NH₂ Methyl or 4-OCH₃-phenyl cyclopropyl 60H m- pyridine C(O)NH— 61 NH₂ Methyl or indole cyclopropyl 62 H Methyl orindoline cyclopropyl 63 NH₂ Methyl or benzofuran cyclopropyl 64 H Methylor 2-F-phenyl cyclopropyl 65 NH₂ Methyl or 4-F-phenyl cyclopropyl 66 HMethyl or dihydrobenzofuran cyclopropyl 67 NH₂ Methyl orcyclohexyl-(CH₂)₂— cyclopropyl 68 NH₂ Methyl or cyclopropyl-(CH₂)₂—cyclopropyl 69 H Methyl or 2-thiophene cyclopropyl 70 NH₂ Methyl or3-thiophene cyclopropyl 71 H Methyl or 2-pyridine cyclopropyl 72 NH₂Methyl or 1-morpholinyl cyclopropyl 73 (CH₃)NH—(CH₂)₂—N— Methyl or1-piperazinyl cyclopropyl 74 (C₂H₅)NH—(CH₂)₂—N— Methyl or 1-piperidinylcyclopropyl

TABLE 2

Ex. No. R¹ R³ R⁶ 75 H Methyl or 2-CH₃-phenyl chloro 76 NH₂ Methyl or4-CF₃-phenyl chloro 77 1-piperidinyl Methyl or 3-CF₃-phenyl chloro 78cyclohexyl-N- Methyl or 6-CH₃-phenyl chloro 79 morpholine-(CH₂)₂—N—Methyl or 2-OCH₃-phenyl chloro 80 (CH₃)₂N—(CH₂)₂—N— Methyl or4-OCH₃-phenyl chloro 81 (C₂H₅)₂N—(CH₂)₂—N— Methyl or pyridine chloro 823-OH-1-pyrrolidinyl Methyl or indole chloro 83 3-amido-1-pyrrolidinylMethyl or indoline chloro 84 4-amido-1-piperidinyl Methyl or benzofuranchloro 85 3-amido-1-piperidinyl Methyl or 2-F-phenyl chloro 864N-CH₃-1-piperizinyl Methyl or 4-F-phenyl chloro 87 H Methyl orDihydrobenzofuran chloro 88 NH₂ Methyl or cyclohexyl-(CH₂)₂— cyclopropyl89 4-CH₃-phenyl Methyl or cyclopropyl-(CH₂)₂— cyclopropyl 90 H Methyl or2-CH₃-phenyl cyclopropyl 91 NH₂ Methyl or 4-CF₃-phenyl cyclopropyl 92 HMethyl or 3-CF₃-phenyl cyclopropyl 93 NH₂ Methyl or 6-CH₃-phenylcyclopropyl 94 3-thiophene Methyl or 2-OCH₃-phenyl cyclopropyl 95 HMethyl or 4-OCH₃-phenyl cyclopropyl 96 NH₂ Methyl or pyridinecyclopropyl 97 1-piperazinyl Methyl or indole cyclopropyl 981-piperidinyl Methyl or indoline cyclopropyl 99 cyclohexyl-N- Methyl orbenzofuran cyclopropyl 100 morpoline-(CH₂)₂—N— Methyl or 2-F-phenylcyclopropyl 101 (CH₃)₂N—(CH₂)₂—N— Methyl or 4-F-phenyl cyclopropyl 102(C₂H₅)₂N—(CH₂)₂—N— Methyl or dihydrobenzofuran cyclopropyl 103 H Methylor 2-CH₃-phenyl cyclopropyl 104 NH₂ Methyl or 4-CF₃-phenyl cyclopropyl105 3-amido-1-piperidinyl Methyl or 3-CF₃-phenyl cyclopropyl 1064-amido-1-piperidinyl Methyl or 6-CH₃-phenyl cyclopropyl 107 H Methyl or2-OCH₃-phenyl cyclopropyl 108 NH₂ Methyl or 4-OCH₃-phenyl cyclopropyl109 H Methyl or pyridine cyclopropyl 110 NH₂ Methyl or indolecyclopropyl 111 H Methyl or indoline cyclopropyl 112 NH₂ Methyl orbenzofuran cyclopropyl 113 H Methyl or 2-F-phenyl cyclopropyl 114 NH₂Methyl or 4-F-phenyl cyclopropyl 115 H Methyl or dihydrobenzofurancyclopropyl 116 NH₂ Methyl or cyclohexyl-(CH₂)₂— cyclopropyl 1171-morpholinyl Methyl or cyclopropyl-(CH₂)₂— cyclopropyl 118 H Methyl or2-CH₃-phenyl cyclopropyl 119 NH₂ Methyl or 4-CF₃-phenyl cyclopropyl 120H Methyl or 3-CF₃-phenyl cyclopropyl 121 NH₂ Methyl or 6-CH₃-phenylcyclopropyl 122 H Methyl or 2-OCH₃-phenyl cyclopropyl 123 NH₂ Methyl or4-OCH₃-phenyl cyclopropyl 124 H Methyl or pyridine cyclopropyl 125 NH₂Methyl or indole cyclopropyl 126 H Methyl or indoline cyclopropyl 127NH₂ Methyl or benzofuran cyclopropyl 128 H Methyl or 2-F-phenylcyclopropyl 129 NH₂ Methyl or 4-F-phenyl cyclopropyl 130 H Methyl ordihydrobenzofuran cyclopropyl 131 NH₂ Methyl or cyclohexyl-(CH₂)₂—cyclopropyl 132 NH₂ Methyl or cyclopropyl-(CH₂)₂— cyclopropyl 133 HMethyl or 2-thiophene cyclopropyl 134 NH₂ Methyl or 3-thiophenecyclopropyl 135 H Methyl or 2-pyridine cyclopropyl 136 NH₂ Methyl or1-morpholinyl cyclopropyl 137 (CH₃)NH—(CH₂)₂—N— Methyl or 1-piperazinylcyclopropyl 138 (C₂H₅)NH—(CH₂)₂—N— Methyl or 1-piperidinyl cyclopropyl

While the examples described above provide processes for synthesizingcompounds of Formulas I and II, other methods may be utilized to preparesuch compounds. Methods involving the use of protecting groups may beused. Particularly, if one or more functional groups, for examplecarboxy, hydroxy, amino, or mercapto groups, are or need to be protectedin preparing the compounds of the invention, because they are notintended to take part in a specific reaction or chemical transformation,various known conventional protecting groups may be used. For example,protecting groups typically utilized in the synthesis of natural andsynthetic compounds, including peptides, nucleic acids, derivativesthereof and sugars, having multiple reactive centers, chiral centers andother sites potentially susceptible to the reaction reagents and/orconditions, may be used.

All process steps described herein can be carried out under knownreaction conditions, preferably under those specifically mentioned, inthe absence of or usually in the presence of solvents or diluents,preferably such as are inert to the reagents used and able to dissolvethese, in the absence or presence of catalysts, condensing agents orneutralizing agents, for example ion exchangers, typically cationexchangers, for example in the H⁺ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from about

−100° C. to about 190° C., preferably from about −80° C. to about 150°C., for example at about −80 to about 60° C., at RT, at about −20 toabout 40° C. or at the boiling point of the solvent used, underatmospheric pressure or in a closed vessel, where appropriate underpressure, and/or in an inert atmosphere, for example, under argon ornitrogen.

Salts may be present in all starting compounds and transients, if thesecontain salt-forming groups. Salts may also be present during thereaction of such compounds, provided the reaction is not therebydisturbed.

The solvents from which those can be selected which are suitable for thereaction in question include, for example, water, esters, typicallylower alkyl-lower alkanoates, e.g. EtOAc, ethers, typically aliphaticethers, e.g. Et₂O, or cyclic ethers, e.g. THF, liquid aromatichydrocarbons, typically benzene or toluene, alcohols, typically MeOH,EtOH, IPA or 1-propanol, nitriles, typically AcCN, halogenatedhydrocarbons, typically CH₂Cl₂, acid amides, typically DMF, bases,typically heterocyclic nitrogen bases, e.g. pyridine, carboxylic acids,typically lower alkanecarboxylic acids, e.g. HOAc, carboxylic acidanhydrides, typically lower alkane acid anhydrides, e.g. aceticanhydride, cyclic, linear, or branched hydrocarbons, typicallycyclohexane, hexane, or isopentane, or mixtures of these solvents, e.g.aqueous solutions, unless otherwise stated in the description of theprocess.

The invention relates also to those forms of the process in which onestarts from a compound obtainable at any stage as a transient speciesand carries out the missing steps, or breaks off the process at anystage, or forms a starting material under the reaction conditions, oruses said starting material in the form of a reactive derivative orsalt, or produces a compound obtainable by means of the processaccording to the invention and processes the said compound in situ. Inthe preferred embodiment, one starts from those starting materials whichlead to the compounds described above as preferred.

The compounds of formula I or II, including their salts, are alsoobtainable in the form of hydrates, or their crystals can include forexample the solvent used for crystallization (present as solvates).

New starting materials and/or intermediates, as well as processes forthe preparation thereof, are likewise the subject of this invention. Inone embodiment, such starting materials are used and reaction conditionsso selected as to enable the preferred compounds to be obtained.Starting materials of the invention, are known, are commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art. In the preparation of starting materials,existing functional groups which do not participate in the reactionshould, if necessary, be protected. Preferred protecting groups, theirintroduction and their removal are described above or in the examples.All remaining starting materials are known, capable of being preparedaccording to known processes, or commercially obtainable; in particular,they can be prepared using processes as described in the examples.

The examples above serve to illustrate various embodiments of theinvention. The tables also contain the method by which these exampleswere prepared, with respect to the various schemes and examplespresented above. The schematic illustrations, detailed description ofthe methods and preparation of compounds of Formulas I or II, andcompounds described above fall within the scope, and serve to exemplifythe scope of compounds contemplated in the invention. These detailedmethod descriptions are presented for illustrative purposes only and arenot intended as a restriction on the scope of the present invention.

Biological Assays

The following assays can be employed to determine the degree of activityof a compound as a C-kit protein kinase modulator. Compounds describedherein have been tested in one or more of these assays, and have shownactivity. Representative compounds of the invention were tested andfound to exhibit IC₅₀ values of at least <10 μM in any one of thedescribed assays, thereby demonstrating and confirming the utility ofthe compounds of the invention as c-kit kinase inhibitors and in theprophylaxis and treatment of c-kit kinase activity-related disorders.

cKIT-Homogeneous Time Resolved Fluorescent (HTRF) Kinase Assay:

The purpose of this assay is to measure the inhibition of cKIT enzymeactivity (autophosphorylation and phosphorylation of substrate) by smallmolecule test compounds. The cKIT HTRF assay begins with cKIT-catalyzedphosphorylation of biotinylated peptide Her-2 (N-GGMEDIYFEFMGGKKK-C) inthe presence of ATP. The cKIT enzyme reaction is comprised of 1 μL ofcompound in 100% DMSO, 15 μL of 2× substrate mix (50 μM ATP and 2 μMbiotinylated Her-2) and 15 μL of 2× cKIT (6.25 μM) (catalytic domain,N-terminal GST tagged, unphosphorylated) in 4 mM DTT all diluted inenzyme buffer (25 mM HEPES pH 7.5, 12.5 mM NaCl, 50 mM MgCl, 0.05% BSA).The reaction incubates for 90 min at RT. 160 Microliters of detectionmixture containing 0.47 μg/mL steptavidin allophycocyanin and 29.7 pMeuropylatedanti-phosphotyrosine Ab (PT66, Perkin Elmer) in HTRF buffer(100 mM Hepes pH 7.5, 100 mM NaCl, 0.1% BSA, 0.05% Tween 20) is thenadded to stop the reaction, by diluting out the enzyme as well as toenable quantitation of phosphorylated Her-2. After 3 h at RT, thedetection reaction is read in a Packard Discovery™ (model BD1000) platereader. The wells are excited with coherent 320 nM light and the ratioof delayed (50 ms post excitation) emissions at 620 nM (native europiumfluorescence) and 665 nm (europium fluorescence transferred toallophycocyanin—an index of substrate phosphorylation) is determined.The proportion of substrate phosphorylated in the kinase reaction in thepresence of compound compared with that phosphorylated in the presenceof DMSO vehicle alone (HI control) is calculated using the formula: %control (POC)=(cpd−average LO)/(average HI−average LO)*100. Data(consisting of POC and inhibitor concentration in μM) is fitted to a4-parameter equation (y=A+((B−A)/(1+((x/C)ˆD))), where A is the minimumy (POC) value, B is the maximum y (POC), C is the x (compoundconcentration) at the point of inflection and D is the slope factor)using a Levenburg-Marquardt non-linear regression algorithm.

Of the compounds tested, exemplary compounds 4 and 6-11 exhibited anaverage IC₅₀ value of 2.0 uM or less in a human HTRF assay, for theinhibition of the c-KIT kinase enzyme. Of the compounds tested,exemplary compounds 4 and 6-10 exhibited an average IC₅₀ value of 100 nMor less in a human HTRF assay, for the inhibition of the c-KIT kinaseenzyme. Of the compounds tested, exemplary compounds 6-8 exhibited anaverage IC₅₀ value of 20 nM or less in a human HTRF assay, for theinhibition of the c-KIT kinase enzyme. Of the compounds tested,exemplary compounds 6-7 exhibited an average IC₅₀ value of 10 nM or lessin a human HTRF assay, for the inhibition of the c-KIT kinase enzyme.

MO7e phosphorylated-cKIT (Tyr721) Electrochemiluminescent Immunoassay:

The purpose of this assay is to test the potency of small moleculecompounds on SCF-stimulated cKIT receptor phosphorylation of tyrosine721 (Tyr721) in MO7e cells. Activation of cKIT upon binding with it'sligand, stem cell factor (SCF), leads to dimerization/oligomerizationand autophosphorylation. Activation of cKIT results in the recruitmentand tyrosine phosphorylation of downstream SH2-containing signalingcomponents—such as the p85 subunit of PI3 kinase (Sattler, M. et al.(1997) J. Biol. Chem. 272, 10248-10253). cKIT phosphorylated at Tyr721binds to the p85 subunit of PI3 kinase (Blume-Jensen, P et al. (2000)Nature Genet. 24, 157-162). MO7e cells are a human megakaryoblasticfactor dependent leukemia cell line (these cells have been confirmed tocarry wild type cKIT receptor). Cells are maintained in growth media(IMDM, 10% HI-FBS, 1XPGS, 5 ng/mL GM-CSF). To measure SCF-induced cKITphosphorylation, cells are washed and resuspended to 3.3E5c/mL in assaymedia (RPMI 1640/4% HI-FBS, 1XPGS) and plated at 30 uL/well for 10000c/well. Small molecule compounds are diluted in 100% DMSO. Cells arepre-incubated with 0.5-2 μL compound for 1 h at RT. 10 Microliters of4XSCF (100 ng/mL) in RT assay media is then added. After 30 minincubation at RT, the cells are lysed with the addition of 20 μL of icecold 3× lysis buffer (20 mM Tris-Cl, 1 mM EDTA, 150 mM NaCl, 1% NP-40, 2mM NaF, 20 mM □-glycerophosphate, 1 mM Na₃VO₄ and 1 Complete Proteinaseinhibitor table/50 mL 1× lysis buffer (Roche Cat # 1697498, in stockroom)). 25 Microliters of lysate is transferred to blocked MSD plates(blocked with 5% BSA in Tris-buffered saline, 0.01% Tween (TBS-T) for 1h with shaking, then washed 3× with TBS-T) coated with anti-cKITantibody (Labvision MS-289). After the plates are incubated with shakingfor 1 h at RT, 25 μL of 10 nM ruthenylated detection antibody (Zymed34-9400) is added and the plate is incubated again with shaking for 1 hat RT. The plates are then washed 3× with TBS-T, 150 μL of MSD ReadBuffer T is added, and the electrochemiluminescence (ECL) reaction isread on the Sector Imager™ 6000. A low voltage is applied to theruthenylated phos-cKIT(Tyr721) immune complexes, which in the presenceof TPA (the active component in the ECL reaction buffer, Read Buffer T),results in a cyclical redox reaction generating light at 620 nm. Theamount of phosphorylated cKIT (Tyr721) in the presence of compoundscompared with that in the presence of vehicle alone (HI control) iscalculated using the formula: % control (POC)=(cpd−average LO)/(averageHI−averageLO)*100. Data (consisting of POC and inhibitor concentrationin μM) is fitted to a 4-parameter equation (y=A+((B−A)/(1+((x/C)ˆD))),where A is the minimum y (POC) value, B is the maximum y (POC), C is thex (cpd concentration) at the point of inflection and D is the slopefactor) using a Levenburg-Marquardt non-linear regression algorithm.

SCF and GM-CSF Stimulated UT7 Proliferation/Survival Assay:

The purpose of this assay is to test the generalanti-proliferative/cytotoxic effect of small molecule compounds on SCFor GM-CSF-stimulated UT-7 cells. Preventing SCF stimulatedproliferation/survival is consistent with an on-mechanism effect whereasinhibition of GM-CSF driven proliferation/survival is indicative ofoff-target effects. UT-7 is a factor dependent human megakaryoblasticleukemia cell line that can be grown in either IL-3, GM-CSF, EPO or SCF(these cells have been confirmed to carry wild type cKIT receptor).Cells are maintained in growth media (IMDM, 10% HI-FBS, 1XPGS, 1 ng/mLGM-CSF). To measure SCF or GM-CSF-induced proliferation, cells arewashed and re-suspended to 5e4 c/mL in assay media (RPMI 1640/4% HI-FBS,1XPGS) and plated at 50 uL/well for 2500 c/well. Small moleculecompounds are first diluted in 100% DMSO, then diluted 1:4 in RT assaymedia. 5 Microliters of 11× SCF (55 ng/mL) or 11×GM-CSF (11 ng/mL) inassay media plus 1 μL of diluted drug are added to the cell plates. Thetreated cells are incubated in a 37° C. humidified incubator with 5% CO₂for 3 days. The amount of ATP is then measured as a surrogate marker forcell viability. This is accomplished by adding 50 μL of Perkin Elmer ATP1 step reagent (as per instructed in the reagent manual, Cat. No.6016739), incubating at RT for 15 min and reading the luminescence witha Perkin Elmer Topcount NXT™HTS (model c384) plate reader. The amount ofSCF or GM-CSF stimulated viable cells in the presence of compoundcompared with in the presence of vehicle alone (HI control) iscalculated using the formula: % control (POC)=(cpd−average LO)/(averageHi−average LO)*100. Data (consisting of POC and inhibitor concentrationin μM) is fitted to a 4-parameter equation (y=A+((B−A)/(1+((x/C)ˆD))),where A is the minimum y (POC) value, B is the maximum y (POC), C is thex (cpd concentration) at the point of inflection and D is the slopefactor) using a Levenburg-Marquardt non-linear regression algorithm.

Of the compounds tested, exemplary compounds 4 and 6-10 exhibited anaverage IC₅₀ value of 1.0 uM or less in in the SCF stimulated UT7proliferation and survival assay, for the inhibition of the c-KIT kinaseenzyme. Of the compounds tested, exemplary compounds 4 and 6-10exhibited an average IC₅₀ value of 150 nM or less in the SCF stimulatedUT7 proliferation and survival assay, for the inhibition of the c-KITkinase enzyme. Of the compounds tested, exemplary compounds 6-7 and 9-10exhibited an average IC₅₀ value of 50 nM or less in the SCF stimulatedUT7 proliferation and survival assay.

Formulation and Modes of Administration/Methods of Use

For the treatment of C-kit mediated diseases including those listedherein, the compounds of the present invention may be administered byseveral different modes, including without limitation, oral, parental,by spray inhalation, rectal, or topical, as discussed herein. The termparenteral as used herein, includes subcutaneous, intravenous,intramuscular, intrasternal, infusion techniques or intraperitonealadministration.

Treatment of diseases and disorders herein is intended to also includetherapeutic administration of a compound of the invention (or apharmaceutical salt, derivative or prodrug thereof), or a pharmaceuticalcomposition medicament comprising said compound, to a subject (i.e., toan animal, preferably a mammal, most preferably a human) believed to bein need of preventative treatment.

Diseases or disorders which may be treated include, without limitation,allergies, mast cell related tumors and other c-kit mediated conditions.Treatment also encompasses administration of the compound, or apharmaceutical composition comprising the compound, to subjects nothaving been diagnosed as having a need thereof, i.e., prophylacticadministration to the subject. Generally, the subject is initiallydiagnosed by a licensed physician and/or authorized medicalpractitioner, and a regimen for prophylactic and/or therapeutictreatment via administration of the compound(s) or compositions of theinvention is suggested, recommended or prescribed.

“Treating” or “treatment of” within the context of the instantinvention, means an alleviation, in whole or in part, of symptomsassociated with a disorder or disease, or halt of further progression orworsening of those symptoms, or prevention or prophylaxis of the diseaseor disorder.

Similarly, as used herein, an “effective amount” or “therapeuticallyeffective amount” of a compound of the invention refers to an amount ofthe compound, or pharmaceutical composition, that alleviates, in wholeor in part, symptoms associated with a disorder or disease, or halts offurther progression or worsening of those symptoms, or prevents orprovides prophylaxis for the disease or disorder. For example, withinthe context of treating patients in need of an inhibitor of C-kit,successful treatment may include a reduction in mast cell mediatedtumor; an alleviation of symptoms related to a fibrotic condition; or ahalting in the progression of an allergic response.

While it may be possible to administer a compound of the inventionalone, in the methods described, the compound administered is generallypresent as an active ingredient in a desired dosage unit formulation,such as pharmaceutically acceptable composition (also referred to as“medicament” herein) containing conventional pharmaceutically acceptablecarriers. Thus, in another embodiment of the invention, there isprovided a pharmaceutical composition comprising a compound of thisinvention in combination with a pharmaceutically acceptable carrier.Acceptable pharmaceutical carriers generally include diluents,excipients, adjuvants and the like as described herein.

A pharmaceutical composition of the invention may comprise an effectiveamount of a compound of the invention or an effective dosage amount (orunit dosage amount) of a compound of the invention. An effective dosageamount of a compound of the invention includes an amount less than,equal to, or greater than an effective amount of the compound. Forexample, a pharmaceutical composition in which two or more unit dosages,such as in tablets, capsules and the like, are required to administer aneffective amount of the compound, or alternatively, a multi-dosepharmaceutical composition, such as powders, liquids and the like, inwhich an effective amount of the compound may be administered byadministering a portion of the composition.

The pharmaceutical compositions may generally be prepared by mixing oneor more compounds of Formula I or II including stereoisomersortautomers, solvates, pharmaceutically acceptable salts, derivatives orprodrugs thereof, with pharmaceutically acceptable carriers, excipients,binders, adjuvants, diluents and the like, to form a desiredadministrable formulation to treat or ameliorate a variety of disordersrelated to the activity of C-kit, particularly autoimmune disease.

Pharmaceutical compositions can be manufactured by methods well known inthe art such as conventional granulating, mixing, dissolving,encapsulating, lyophilizing, emulsifying or levigating processes, amongothers.

The compositions can be in the form of, for example, granules, powders,tablets, capsules, syrup, suppositories, injections, emulsions, elixirs,suspensions or solutions. The instant compositions can be formulated forvarious routes of administration, for example, by oral administration,by transmucosal administration, by rectal administration, orsubcutaneous administration as well as intrathecal, intravenous,intramuscular, intraperitoneal, intranasal, intraocular orintraventricular injection. The compound or compounds of the instantinvention can also be administered in a local rather than a systemicfashion, such as injection as a sustained release formulation.

Besides those representative dosage forms described herein,pharmaceutically acceptable excipients and carriers are generally knownto those skilled in the art and are thus included in the instantinvention. Such excipients and carriers are described, for example, in“Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (2000);and “Pharmaceutics The Science of Dosage Form Design, 2^(nd) Ed.(Aulton, ed.) Churchill Livingstone (2002). The following dosage formsare given by way of example and should not be construed as limiting theinvention.

For oral, buccal, and sublingual administration, powders, suspensions,granules, tablets, pills, capsules, gelcaps, and caplets are acceptableas solid dosage forms. These can be prepared, for example, by mixing oneor more compounds of the instant invention, or stereoisomers, solvates,prodrugs, pharmaceutically acceptable salts or tautomers thereof, withat least one additive or excipient such as a starch or other additiveand tableted, encapsulated or made into other desirable forms forconventional administration. Suitable additives or excipients aresucrose, lactose, cellulose sugar, mannitol, maltitol, dextran,sorbitol, starch, agar, alginates, chitins, chitosans, pectins,tragacanth gum, gum arabic, gelatins, collagens, casein, albumin,synthetic or semi-synthetic polymers or glycerides, methyl cellulose,hydroxypropylmethyl-cellulose, and/or polyvinylpyrrolidone. Optionally,oral dosage forms can contain other ingredients to aid inadministration, such as an inactive diluent, or lubricants such asmagnesium stearate, or preservatives such as paraben or sorbic acid, oranti-oxidants such as ascorbic acid, tocopherol or cysteine, adisintegrating agent, binders, thickeners, buffers, sweeteners,flavoring agents or perfuming agents. Additionally, dyestuffs orpigments may be added for identification. Tablets and pills may befurther treated with suitable coating materials known in the art.

Liquid dosage forms for oral administration may be in the form ofpharmaceutically acceptable emulsions, syrups, elixirs, suspensions,slurries and solutions, which may contain an inactive diluent, such aswater. Pharmaceutical formulations may be prepared as liquid suspensionsor solutions using a sterile liquid, such as, but not limited to, anoil, water, an alcohol, and combinations of these. Pharmaceuticallysuitable surfactants, suspending agents, emulsifying agents, and thelike may be added for oral or parenteral administration.

For nasal administration, the pharmaceutical formulations may be a sprayor aerosol containing an appropriate solvent and optionally othercompounds such as, but not limited to, stabilizers, antimicrobialagents, antioxidants, pH modifiers, surfactants, bioavailabilitymodifiers and combinations of these. A propellant for an aerosolformulation may include compressed air, nitrogen, carbon dioxide, or ahydrocarbon based low boiling solvent. The compound or compounds of theinstant invention are conveniently delivered in the form of an aerosolspray presentation from a nebulizer or the like.

Injectable dosage forms for parenteral administration generally includeaqueous suspensions or oil suspensions, which may be prepared using asuitable dispersant or wetting agent and a suspending agent. Injectableforms may be in solution phase or a powder suitable for reconstitutionas a solution. Both are prepared with a solvent or diluent. Acceptablesolvents or vehicles include sterilized water, Ringer's solution, or anisotonic aqueous saline solution. Alternatively, sterile oils may beemployed as solvents or suspending agents. Typically, the oil or fattyacid is non-volatile, including natural or synthetic oils, fatty acids,mono-, di- or tri-glycerides. For injection, the formulations mayoptionally contain stabilizers, pH modifiers, surfactants,bioavailability modifiers and combinations of these. The compounds maybe formulated for parenteral administration by injection such as bybolus injection or continuous infusion. A unit dosage form for injectionmay be in ampoules or in multi-dose containers.

For rectal administration, the pharmaceutical formulations may be in theform of a suppository, an ointment, an enema, a tablet or a cream forrelease of compound in the intestines, sigmoid flexure and/or rectum.Rectal suppositories are prepared by mixing one or more compounds of theinstant invention, or pharmaceutically acceptable salts or tautomers ofthe compound, with acceptable vehicles, for example, cocoa butter orpolyethylene glycol, which is solid phase at room temperature but liquidphase at those temperatures suitable to release a drug inside the body,such as in the rectum. Various other agents and additives may be used inthe preparation of suppositories as is well known to those of skill inthe art.

The formulations of the invention may be designed to be short-acting,fast-releasing, long-acting, and sustained-releasing as described below.Thus, the pharmaceutical formulations may also be formulated forcontrolled release or for slow release. The instant compositions mayalso comprise, for example, micelles or liposomes, or some otherencapsulated form, or may be administered in an extended release form toprovide a prolonged storage and/or delivery effect. Therefore, thepharmaceutical formulations may be compressed into pellets or cylindersand implanted intramuscularly or subcutaneously as depot injections oras implants such as stents. Such implants may employ known inertmaterials such as silicones and biodegradable polymers.

Specific dosages may be adjusted depending on conditions of disease, theage, body weight, general health conditions, sex, and diet of thesubject, dose intervals, administration routes, excretion rate, andcombinations of drugs. Any of the above dosage forms containingeffective amounts are well within the bounds of routine experimentationand therefore, well within the scope of the instant invention.

A therapeutically effective dosage amount or dose may vary dependingupon the route of administration and dosage form. Typically, thecompound or compounds of the instant invention are selected to provide aformulation that exhibits a high therapeutic index. The therapeuticindex is the dose ratio between toxic and therapeutic effects which canbe expressed as the ratio between LD₅₀ and ED₅₀. The LD₅₀ is the doselethal to 50% of the population and the ED₅₀ is the dose therapeuticallyeffective in 50% of the population. The LD₅₀ and ED₅₀ are determined bystandard pharmaceutical procedures in animal cell cultures orexperimental animals.

The dosage regimen for treating C-kit mediated diseases with thecompounds of this invention and/or compositions of this invention isbased on a variety of factors, including the type of disease, the age,weight, sex, medical condition of the patient, the severity of thecondition, the route of administration, and the particular compoundemployed. Thus, the dosage regimen may vary widely, but can bedetermined routinely using standard methods. Dosage levels of the orderfrom about 0.01 mg to 30 mg per kilogram of body weight per day,preferably from about 0.1 mg to 10 mg/kg, more preferably from about0.25 mg to 1 mg/kg are useful for all methods of use disclosed herein.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more preferably from about 5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose. A suitable topicaldose of active ingredient of a compound of the invention is 0.1 mg to150 mg administered one to four, preferably one or two times daily. Fortopical administration, the active ingredient may comprise from 0.001%to 10% w/w, e.g., from 1% to 2% by weight of the formulation, althoughit may comprise as much as 10% w/w, but preferably not more than 5% w/w,and more preferably from 0.1% to 1% of the formulation.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. The pharmaceutically active compoundsof this invention can be processed in accordance with conventionalmethods of pharmacy to produce medicinal agents for administration topatients, including humans and other mammals.

While the compounds of the present invention can be administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or with one or more otheragents. When administered as a combination, the therapeutic agents canbe formulated and given to the subject as a single composition or thecombination of therapeutic agents can be formulated and given to thesubject as separate compositions that are given at the same time ordifferent times.

Treatment may also include administering the pharmaceutical formulationsof the present invention in combination with other therapies. Forexample, the compounds and pharmaceutical formulations of the presentinvention may be administered before, during, or after surgicalprocedure and/or radiation therapy. Alternatively, the compounds of theinvention can also be administered in conjunction with otheranti-proliferative agents including those used in antisense and genetherapy.

The methods and compositions of the present invention may comprise acombination with another kinase inhibitor. Although the presentinvention is not limited to any particular kinase, kinase inhibitorscontemplated for use include, without limitation, tyrphostin AG490(2-cyano-3-(3,4-dihydroxyphenyl)-N-(benzyl)-2-propenamide), Iressa(ZD1839; Astra Zeneca); Gleevec (STI-571 or imatinib mesylate;Novartis); SU5416 (Pharmacia Corp./Sugen); and Tarceva (OSI-774;Roche/Genentech/OSI Pharmaceuticals).

The foregoing description is merely illustrative of the invention and isnot intended to limit the invention to the disclosed compounds,compositions and methods. Variations and changes, which are obvious toone skilled in the art, are intended to be within the scope and natureof the invention, as defined in the appended claims. From the foregoingdescription, one skilled in the art can easily ascertain the essentialcharacteristics of this invention, and without departing from the spiritand scope thereof, can make various changes and modifications of theinvention to adapt it to various usages and conditions. All patents andother publications recited herein are hereby incorporated by referencein their entireties.

1. A compound of Formula I:

or a stereoisomer or a pharmaceutically acceptable salt thereof, whereinone of A¹, A² and A³ is N and the other two of A¹, A² and A³ is CR²; oreach of A¹, A² and A³, independently, is CR²; R¹ is —NR⁷R⁷, —NR⁷R⁸,—NR⁹R⁹, —C(O)NR⁷, —C(O)NR⁹, —NR²C(O)R⁷, —NR²C(O)R⁹, —NR²C(O)NR⁷,—NR²C(O)NR⁹, —S(O)₂NR⁷, —S(O)₂NR⁹ or —NR²S(O)₂NR⁷; or R¹ is a partiallyor fully saturated or unsaturated 3-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, and wherein eachring of said ring system is optionally substituted independently with1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹ or a partially orfully saturated or unsaturated 5-6 membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-5 substituents of R⁹;alternatively, R¹ and A¹ taken together form a saturated or partially orfully unsaturated 5-6 membered ring of carbon atoms optionally including1-4 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-5 substituents of oxo, NR⁹R⁹, OR⁹, SR⁹,C(O)R⁹ or R⁹; each R², independently, is H, halo, haloalkyl,NO₂,C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, CN, OH, —O—C₁₋₈alkyl,—O-haloalkyl, SH, —S—C₁₋₈alkyl, NH₂, —NH—C₁₋₈alkyl, —N—(C₁₋₈alkyl)₂ or—C(O)—C₁₋₈alkyl, wherein the C₁₋₈-alkyl, C₂₋₈-alkenyl and C₂₋₈-alkynyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with one or more substituents of R⁹; R³, at eachoccurrence, is H, halo, haloalkyl, NO₂, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, CN, OH, —O—C₁₋₈alkyl, —O-haloalkyl, SH, —S—C₁₋₈alkyl, NH₂,—NH—C₁₋₈alkyl, —N—(C₁₋₈alkyl)₂ or —C(O)—C₁₋₈alkyl, wherein theC₁₋₈-alkyl, C₂₋₄-alkenyl and C₂₋₈-alkynyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of R⁹; R⁴ is H, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynylor CN; R⁵ is H, C₁₋₈alkyl, C₂₋₄alkenyl, C₂₋₈alkynyl or CN; R⁶ is C(O)R⁷,COOR⁷, C(O)NR⁷R⁷, C(O)NR⁷R⁸, S(O)₂R⁷, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl or C₂₋₁₀-alkynyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl and C₂₋₁₀-alkynyl optionally comprising 1-4 heteroatomsselected from N, O and S and optionally substituted with one or moresubstituents of R⁸ or R⁹; or R⁶ is a partially or fully saturated orunsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, and wherein each ring of said ring system is optionallysubstituted independently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹,SR⁹, C(O)R⁹ or a partially or fully saturated or unsaturated 5-6membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-5 substituents of R⁹; R⁷ is H, C₁₋₈-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl, each of the C₁₋₈-alkyl,C₂₋₄-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl and C₄₋₈-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with one or more substituents of NR⁸R⁹, NR⁹R⁹,OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹,C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹,NR⁹(COOR⁸), NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹,S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸,NR⁹S(O)₂R⁹ or R⁹; R⁸ is a partially or fully saturated or unsaturated3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 memberedtricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, and wherein each ring of said ring system is optionallysubstituted independently with 1-3 substituents of R⁹, oxo, NR⁹R⁹, OR⁹,SR⁹, C(O)R⁹ or a partially or fully saturated or unsaturated 5-6membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-3 substituents of R⁹; alternatively, R⁷ and R⁸ taken together form asaturated or partially or fully unsaturated 5-6 membered ring of carbonatoms optionally including 1-3 heteroatoms selected from O, N, or S, andthe ring optionally substituted independently with 1-3 substituents ofR⁹; and R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—NHC(O)C₁₋₈-alkyl, C₁₋₈-alkyl, C₂₋₄-alkenyl, C₂₋₈-alkynyl,C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl, C₁₋₈alkylamino-, C₁₋₈-dialkylamino-,C₁₋₈-alkoxyl, C₁₋₈-thioalkoxyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₈alkyl, C₂₋₈-alkenyl,C₂₋₈-alkynyl, C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl, C₁₋₈-alkylamino-,C₁₋₈-dialkylamino-, C₁₋₈-alkoxyl, C₁₋₈-thioalkoxyl and ring of said ringsystem is optionally substituted independently with 1-3 substituents ofhalo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl,tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine,propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl orphenyl.
 2. The compound of claim 1 wherein A¹ is N and each of A² andA³, independently, is CR².
 3. The compound of claim 1 wherein each ofA¹, A² and A³ is CR².
 4. The compound of claim 1 wherein R¹ is —NR⁷R⁷,—NR⁷R⁸, —NR⁹R⁹, —C(O)NR⁷, —C(O)NR⁹, —NR²C(O)R⁷, —NR²C(O)R⁹, —NR²C(O)NR⁷,—NR²C(O)NR⁹, —S(O)₂NR⁷, —S(O)₂NR⁹ or —NR²S(O)₂NR⁷⁷.
 5. The compound ofclaim 1 wherein each R², independently, is H, F, Br, Cl, I, CF₃, CH₂CF₃,NO₂, C₁₋₈alkyl, CN, OH, —OCH₃, —OC₂H₅, —OCF₃, NH₂, —NH—C₁₋₆alkyl or—N—(C₁₋₈alkyl)₂.
 6. The compound of claim 1 wherein R⁶ is phenyl,naphthyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl, thiophenyl,furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, phthalazinyl, thieno-pyrazolyl,imidazolyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl,isoxazolyl, isothiazolyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl,indolyl, azaindolyl, isoindolyl, indazolyl, benzofuranyl,dihydrobenzofuranyl, benzothiophenyl, benzimidazolyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl or cyclohexyl, each of which isoptionally substituted independently with 1-5 substituents of R⁹.
 7. Thecompound of claim 1 wherein R⁶ is a C₁₋₁₀-alkyl substituted with one ofa phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, benzoxazolyl,benzothiazolyl, benzoxadiazolyl, indolyl, azaindolyl, isoindolyl,indazolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl,benzimidazolyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl or acyclohexyl ring, the ring optionally substituted with 1-5 substituentsof R⁹.
 8. The compound of claim 1 wherein A¹ is N and each of A² and A³,independently, is CR²; R¹ is —NR⁷R⁷, —NR⁷R⁸, —NR⁹R⁹, —C(O)NR⁷, —C(O)NR⁹,—NR²C(O)R⁷, —NR²C(O)R⁹, —NR²C(O)NR⁷, —NR²C(O)NR⁹, —S(O)₂NR⁷, —S(O)₂NR⁹or —NR²S(O)₂NR⁷⁷; each R², independently, is H, F, Br, Cl, I, CF₃,CH₂CF₃, NO₂, C₁₋₈alkyl, CN, OH, —OCH₃, —OC₂H₅, —OCF₃, NH₂, —NH—C₁₁alkylor —N—(C₁₋₈alkyl)₂; R³ and R⁴, at each occurrence, is H, C₁₋₈alkyl orCN; and R⁶ is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl,pyridazinyl, thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl,quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, benzoxazolyl,benzothiazolyl, benzoxadiazolyl, indolyl, azaindolyl, isoindolyl,indazolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl,benzimidazolyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl orcyclohexyl, each of which is optionally substituted independently with1-5 substituents of R⁹.
 9. The compound of claim 1 having a Formula II

or a stereoisomer or a pharmaceutically acceptable salt thereof, whereinR¹ is —NR⁷R⁷, —NR⁷R⁸, —NR⁹R⁹, —C(O)NR⁷, —C(O)NR⁹, —NR²C(O)R⁷,—NR²C(O)R⁹, —NR²C(O)NR⁷, —NR²C(O)NR⁹, —S(O)₂NR⁷, —S(O)₂NR⁹ or—NR²S(O)₂NR⁷; or R¹ is a partially or fully saturated or unsaturated 3-8membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclicring system, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,and wherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹or a partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and optionally substituted independently with 1-5 substituents of R⁹;each R², independently, is H, halo, haloalkyl, NO₂,C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, CN, OH, —O—C₁₋₈alkyl, —O-haloalkyl, SH,—S—C₁₋₈alkyl, NH₂, —NH—C₁₋₈alkyl, —N—(C₁₋₈alkyl)₂ or —C(O)—C₁₋₈alkyl,wherein the C₁₋₈-alkyl, C₂₋₈-alkenyl and C₂₋₈-alkynyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with one or more substituents of R⁹; R³ is H, halo,haloalkyl, NO₂, C₁₋₈alkyl, CN, OH, —O—C₁₋₈alkyl, —O-haloalkyl, SH,—S—C₁₋₈alkyl, NH₂, —NH—C₁₋₈alkyl or —N—(C₁₋₈alkyl)₂; R⁵ is H, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl or CN; —R⁶ is C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl orC₂₋₁₀-alkynyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl and C₂₋₁₀-alkynyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with one or more substituents of R⁸ or R⁹; or R⁶is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹or a partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and optionally substituted independently with 1-5 substituents of R⁹;R⁷ is H, C₁₋₈alkyl, C₂₋₄-alkenyl, C₂₋₈-alkynyl, C₃₋₄-cycloalkyl orC₄₋₄-cycloalkenyl, each of the C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₃₋₈-cycloalkyl and C₄₋₈-cycloalkenyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸,OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸,NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹),OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹,NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹ or R⁹; R⁸ is apartially or fully saturated or unsaturated 3-8 membered monocyclic,6-12 membered bicyclic, or 7-14 membered tricyclic ring system, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, and wherein eachring of said ring system is optionally substituted independently with1-3 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹ or a partially orfully saturated or unsaturated 5-6 membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-3 substituents of R⁹;alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-3 substituents of R⁹; and —R⁹ is H,halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₈-alkyl, C₂₋₄-alkenyl,C₂₋₈-alkynyl, C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl, C₁₋₈alkylamino-,C₁₋₈-dialkylamino-, C₁₋₈-alkoxyl, C₁₋₈-thioalkoxyl or a saturated orpartially or fully unsaturated 5-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₈alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl, C₁₋₄-alkylamino-, C₁₋₈-dialkylamino-, C₁₋₈alkoxyl,C₁₋₈-thioalkoxyl and ring of said ring system is optionally substitutedindependently with 1-3 substituents of halo, haloalkyl, CN, NO₂, NH₂,OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine,ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.
 10. The compound of claim 9 whereinR³ is halo, haloalkyl, C₁₋₈alkyl, CN, OH, —O—C₁₋₈alkyl, —O-haloalkyl,—NH—C₁₋₈alkyl or —N—(C₁₋₈alkyl)₂; R⁵ is H; and R⁶ is phenyl, naphthyl,pyridyl, pyrimidinyl, triazinyl, pyridazinyl, thiophenyl, furyl,tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, phthalazinyl, thieno-pyrazolyl,imidazolyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl,isoxazolyl, isothiazolyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl,indolyl, azaindolyl, isoindolyl, indazolyl, benzofuranyl,dihydrobenzofuranyl, benzothiophenyl, benzimidazolyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl or cyclohexyl, each of which isoptionally substituted independently with 1-5 substituents of R⁹. 11.The compound of claim 1, and pharmaceutically acceptable salts thereof,selected from:3-((2-amino-5-pyrimidinyl)ethynyl)-1-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-4-methyl-2(1H)-pyridinone;3-((2-amino-5-pyrimidinyl)ethynyl)-1-(3,4-dimethylphenyl)-4-methyl-2(1H)-pyridinone;1-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-2(1H)-pyridinone;3-((2-amino-5-pyrimidinyl)ethynyl)-1-(2,3-dihydro-1-benzofuran-5-yl)-4-methyl-2(1H)-pyridinone;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-1-(3-((trifluoromethyl)oxy)phenyl)-2(1H)-pyridinone;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-1-(3-(trifluoromethyl)phenyl)-2(1H)-pyridinone;and4-methyl-3-(3-pyridinylethynyl)-1-(3-(trifluoromethyl)phenyl)-2(1H)-pyridinone.12. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound according to claim
 1. 13. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound according to claim
 9. 14. A method of treating orpreventing an abnormal condition in a subject, said abnormal conditionis associated with an aberration in a signal transduction pathway ofc-kit kinase, the method comprising administering to the subject aneffective dosage amount of a compound according to claim
 1. 15. Themethod of claim 14 wherein the condition is selected from the groupconsisting of fibrotic disease, mastocytosis, the presence of one ormore mast cell tumors, severe asthma, rheumatoid arthritis, scleroderma,multiple sclerosis and allergy associated chromic rhinitis.
 16. Themethod of claim 14 wherein the condition is selected from the groupconsisting of over-production of histamine, autoimmune disease,mastocytosis, small cell lung cancer, acute myelocytic leukemia, acutelymphocytic leukemia, myelodysplastic syndrome, chronic myelogenusleukemia, colorectal carcinoma, gastric carcinoma, gastrointestinalstromal tumor, testicular cancer, glioblstoma, astrocytoma, fibroticdiseases including without limitation, idiopathic pulmonary fibrosis, ora combination thereof in a subject.
 17. A method of treating a fibroticdisease in a subject, the method comprising administering to the subjectan effective dosage amount of a compound according to claim
 1. 18. Themethod of claim 17 wherein the fibrotic disease is idiopathic pulmonaryfibrosis.
 20. A process for synthesizing a compound of claim 1, theprocess comprising the step of reacting a compound of Formula 4

wherein R³, R⁴, R⁵ and R⁶ are as defined in claim 1, with a compoundhaving a general Formula 5

, wherein A¹, A², A³ and R¹ are as defined in claim 1, in the presenceof CuI and palladium to make a compound of Formula I of claim 1.